The insulin-like growth factor-I receptor (IGF-IR) activation mediates cell proliferation and prevents apoptosis. It also has other important cellular effects, mediated by downstream signaling pathways. A. IGF-1R activation stimulates cell cycle progression and plays a role in DNA repair. IGF-1R activation stimulates the expression of 14-3-3 sigma a protein previously considered to regulate cell cycle G2/M arrest. MCF-7 cells were studied and the level of 14-3-3 sigma was reduced using siRNA which led to a delay in S phase of the cell cycle in IGF-1-treated cells, suggesting that 14-3-3 sigma is a mediator of the IGF-1-induced cell cycle proliferation. B. The MCF-7 cells were also used to study the interaction of the estrogen receptor and the IGF-I receptor. Estradiol and IGF-I stimulation of MCF-7 cells showed an early synergistic effect on proliferation, suggesting a non-genomic effect on the estrogen receptor. The synergistic effects were seen at both early and late signaling events of the IGF-I receptor signaling cascade and also in cell cycle events. Thus the IGF-I receptor is essential for cellular proliferation and anti-apoptosis, as well as other important cellular functions.